1. Field of the Invention
The present invention relates to the treatment of mesothelioma.
2. Description of the Background Art
Taurolidine (Bis-(1,1-dioxoperhydro-1,2,4-thiadiazinyl-4)methane) was developed by Geistlich Pharma. It is a white crystalline substance, water soluble up to 2%. It is made up of two molecules of taurinamid and three molecules formaldehyde forming a two-ringed structure bridged by a methylene group.
Taurolidine has primarily an antibiotic and anti-endotoxin effect. This effect of taurolidine is mediated by its active metabolites, which are donators of active methylol-groups: Methylol-Taurultam and Methylol-Taurinamide. The active methylol groups inactivate by reacting with the cell wall of bacteria and with the primary amino groups of endotoxins.
Methylol transfer agents, such as the antibacterial and anti-toxin drug taurolidine and the related product taurultam, have been shown to exert a modifying effect on the toxicity of tumor necrosis factor (TNF) which is used, inter alia, in the treatment of tumors. Furthermore, the action of methylol transfer agents has been shown to be selective in that the growth of normal cell-lines was not significantly inhibited.
Taurolidine acts by transferring three methylol groups at the site of action, taurultam being an intermediate metabolite which itself transfers a single methylol group with liberation of the very well tolerated compound taurinamide. Thus, the two compounds act by essentially the same mechanism. It should be noted that methylol transfer is to be contrasted with methyl transfer which is characteristic of many highly toxic anti-tumor drugs. Taurolidine and taurultam have low toxicity and are not cytotoxic against normal cells.
In an approach to increase effectiveness of chemotherapy by increasing the concentration of the agent within the tumor and the duration of exposure, chemotherapeutic agents are administered locally relying on diffusion for their distribution. In local therapy, the antineoplastic agent is introduced into the tumor itself or the area around the tumor. The resulting pressure gradient leads to diffusion of the antineoplastic agent into the tumor. This mode of administration not only increases the concentration of the agent within the tumor but also results in much lower concentrations in other tissues compared to systemic administration.
One such approach of local tumor treatment is so-called convection-enhanced drug delivery (CEED) in which the drug is infused into the tumor or the surrounding tissue. The drug is distributed by convective transport, a mode of administration which requires placement of a catheter in most cases. Furthermore, taurolidine solutions have been used as instillation or rinsing solutions of the abdominal cavity in cases of peritonitis. In post-operative instillations, conscious patients have reported as a side-effect irritation and sometimes burning sensations.
Malignant pleural mesothelioma is an uncommon tumor that causes about 1500 deaths per year in the US. However, although it is uncommon, it has been in recent years recorded with increasing frequency. It has gained considerable attention in the press from its association with the environmental carcinogen, asbestos. Mesothelioma associated with exposure to asbestos manifests itself only after a long latency period—from the time of initial exposure to 20 to 40 years or more. Due to considerable exposure to asbestos years ago, it is anticipated that mesothelioma will be a significant health problem for decades to come.
Currently, in Germany for example, 900 new cases of this illness are to be expected each year. Because of the connection of the disease with the use of asbestos-contaminated labor materials and the very long latency stage, it is an exponential increase of new cases is expected.
Therapeutic options extend from watchful waiting to palliative or radical multimodal therapeutic concepts.